Alnylam announces new pre-clinical results with DC for ALN-CC5 to treat complement-mediated diseases

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today new pre-clinical results with its Development Candidate (DC) for ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases. These results were presented at the 7th International Conference on Complement Therapeutics being held June 6 - 11, 2014, in Olympia, Greece. New data demonstrate that ALN-CC5 led to an up to 98.7% knockdown of serum C5 and an up to 96.8% inhibition of complement activity in non-human primates (NHP) with weekly subcutaneous dose administration. Alnylam believes that ALN-CC5 - part of the company's "Alnylam 5x15" product strategy - could represent a novel approach for the treatment of complement-mediated diseases, with a potentially competitive profile compared with intravenously administered anti-C5 monoclonal antibody therapy. ALN-CC5 utilizes the company's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. ESC-GalNAc conjugates are a clinically validated platform based on recent preliminary Phase 1 study results from the company's ALN-AT3 program in development for the treatment of hemophilia. The company is on track to file its ALN-CC5 IND or IND equivalent in late 2014, and is now guiding that it expects to present initial clinical results in mid-2015.

"These new pre-clinical data with our recently selected Development Candidate for ALN-CC5 demonstrate potent C5 knockdown and robust inhibition of complement activity in NHPs with weekly subcutaneous dosing. We believe that these are promising results since an over 80% inhibition of complement activity has been shown to be associated with clinical benefit. Further, comparative studies in a mouse arthritis model showed ALN-CC5 to be as effective as an anti-C5 antibody in reducing disease activity, demonstrating a necessary and sufficient role for liver-expressed C5 in localized complement-mediated disease," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "ALN-CC5 employs our ESC-GalNAc-siRNA conjugate platform that has recently been validated in preliminary data from human studies and where we observe a further ten-fold increase in potency as compared with studies in NHPs. Accordingly, we believe we are seeing the emergence of a compelling therapeutic profile for ALN-CC5, which could make it competitive with anti-C5 monoclonal antibody therapy. We look forward to filing an IND or IND-equivalent by the end of this year, and are now guiding that we expect to present initial clinical results in mid-2015."

In a presentation titled "RNAi-Mediated C5 Silencing for Complement Inhibition," Alnylam scientists presented new pre-clinical data with ALN-CC5. In NHP studies, weekly subcutaneous doses of ALN-CC5 at 5 mg/kg led to serum C5 knockdown of up to 98.7% (mean of 97.9 +/- 0.7%), as well as inhibition of complement activity of up to 91.3% (mean of 84.9 +/- 7.1%) by serum hemolytic activity assay and up to 96.8% (mean of 94.6. +/- 1.8%) by complement alternative pathway (CAP) ELISA. Based on early human translational data for ESC-GalNAc conjugates, weekly dosing at less than 1 mg/kg is expected to result in similar effects in humans. The observed inhibitory effect toward complement activity is notable since an over 80% level of complement inhibition has been shown to yield clinical benefit in paroxysmal nocturnal hemoglobinuria (PNH) based on published data with eculizumab, an intravenously administered monoclonal antibody that binds to serum C5 (Hillmen et al.,N Engl J Med 2004,350:552-559). The company is continuing dosing in the primate study to explore twice-monthly and once-monthly subcutaneous dosing regimens, and expects to report additional pre-clinical data later this year. In addition, in vitro reconstitution studies in human serum were performed to evaluate the potential anti-C5 monoclonal antibody (anti-C5 mAb) dose sparing effects of ALN-CC5. Specifically, in serum in which C5 was reduced to 5% of normal (i.e., a level corresponding to 95% C5 knockdown with RNAi), the concentration of anti-C5 mAb required to achieve 80% inhibition of hemolytic activity was found to be reduced approximately 20-fold. This lower concentration requirement could reduce frequent dose requirements and the high costs of anti-C5 antibody therapy. Finally, results were presented from a study comparing subcutaneous doses of ALN-CC5 to a high, intravenously administered dose of an anti-C5 mAb in a mouse anti-collagen antibody induced arthritis (CAIA) model. Results showed that C5 knockdown with ALN-CC5 was as effective as the anti-C5 antibody in reducing clinical disease activity, with both treatments resulting in an approximately 80% reduction in clinical disease activity score. Moreover, ALN-CC5 maintained its knockdown effect toward C5 following lipopolysaccharide (LPS) treatment, showing the ability of RNAi to blunt induction of C5 as part of an inflammatory response. These results demonstrate that knockdown of liver-derived C5 should be fully sufficient to achieve a therapeutic effect, and show the absence of a significant role for local complement production in this disease model.

"The complement system evolved as part of the innate immune system and plays a key role in host defenses. Dysregulation of the complement system can lead to serious complications in a wide range of human diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and neuromyelitis optica," said Anita Hill, MBChB (Hons), MRCP, FRCPath, Ph.D., Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Honorary Senior Lecturer at the University of Leeds. "I am very encouraged by these pre-clinical data showing potent and durable knockdown of serum C5 with robust inhibition of complement activity using a subcutaneously administered RNAi therapeutic. If these results can be extended to the clinical setting, I believe that they could represent an attractive therapeutic strategy and potential new treatment option for patients with complement-mediated diseases."

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